We have derived from normal human, mouse, and rat postnatal bone marrow primitive, multipotent adult progenitor cells (MAPCs) that can differentiate into most mesodermal cells and neuroectodermal cells in vitro and into all embryonic lineages in vivo. Here, we show that MAPCs can also differentiate into hepatocyte-like cells in vitro. Human, mouse, and rat MAPCs, cultured on Matrigel with FGF-4 and HGF, differentiated into epithelioid cells that expressed hepatocyte nuclear factor-3β (HNF-3β), GATA4, cytokeratin 19 (CK19), transthyretin, and α-fetoprotein by day 7, and expressed CK18, HNF-4, and HNF-1α on days 14–28. Virtually all human, as well as a majority of rodent cells stained positive for albumin and CK18 on day 21; 5% (rodent) to 25% (human) cells were binucleated by day 21. These cells also acquired functional characteristics of hepatocytes: they secreted urea and albumin, had phenobarbital-inducible cytochrome p450, could take up LDL, and stored glycogen. MAPCs, which can be expanded in vitro and maintained in an undifferentiated state for more than 100 population doublings, can thus differentiate into cells with morphological, phenotypic, and functional characteristics of hepatocytes. MAPCs may therefore be an ideal cell for in vivo therapies for liver disorders or for use in bioartificial liver devices.

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Multipotent adult progenitor cells from bone marrow differentiate into functional hepatocyte-like cells.

Animal models are commonly used in the preclinical development of new drugs to predict the metabolic behaviour of new compounds in humans. It is, however, important to realise that humans differ from animals with regards to isoform composition, expression and catalytic activities of drug-metabolising enzymes. In this review the authors describe similarities and differences in this respect among the different species, including man. This may be helpful for drug researchers to choose the most relevant animal species in which the metabolism of a compound can be studied for extrapolating the results to humans. The authors focus on CYPs, which are the main enzymes involved in numerous oxidative reactions and often play a critical role in the metabolism and pharmacokinetics of xenobiotics. In addition, induction and inhibition of CYPs are compared among species. The authors conclude that CYP2E1 shows no large differences between species, and extrapolation between species appears to hold quite well. In contrast, the species-specific isoforms of CYP1A, -2C, -2D and -3A show appreciable interspecies differences in terms of catalytic activity and some caution should be applied when extrapolating metabolism data from animal models to humans.

Species differences between mouse, rat, dog, monkey and human CYP-mediated drug metabolism, inhibition and induction.

MicroRNAs (miRNAs) are endogenous ∼23 nt RNAs that play important gene-regulatory roles in animals and plants by pairing to the mRNAs of protein-coding genes to direct their posttranscriptional repression. This review outlines the current understanding of miRNA target recognition in animals and discusses the widespread impact of miRNAs on both the expression and evolution of protein-coding genes.

MicroRNAs: Target Recognition and Regulatory Functions

Sex differences in pharmacokinetics and pharmacodynamics characterize many drugs and contribute to individual differences in drug efficacy and toxicity. Sex-based differences in drug metabolism are the primary cause of sex-dependent pharmacokinetics and reflect underlying sex differences in the expression of hepatic enzymes active in the metabolism of drugs, steroids, fatty acids and environmental chemicals, including cytochromes P450 (P450s), sulfotransferases, glutathione transferases, and UDP-glucuronosyltransferases. Studies in the rat and mouse liver models have identified more than 1000 genes whose expression is sex-dependent; together, these genes impart substantial sexual dimorphism to liver metabolic function and pathophysiology. Sex differences in drug metabolism and pharmacokinetics also occur in humans and are due in part to the female-predominant expression of CYP3A4, the most important P450 catalyst of drug metabolism in human liver. The sexually dimorphic expression of P450s and other liver-expressed genes is regulated by the temporal pattern of plasma growth hormone (GH) release by the pituitary gland, which shows significant sex differences. These differences are most pronounced in rats and mice, where plasma GH profiles are highly pulsatile (intermittent) in male animals versus more frequent (nearly continuous) in female animals. This review discusses key features of the cell signaling and molecular regulatory mechanisms by which these sex-dependent plasma GH patterns impart sex specificity to the liver. Moreover, the essential role proposed for the GH-activated transcription factor signal transducer and activator of transcription (STAT) 5b, and for hepatic nuclear factor (HNF) 4α, as mediators of the sex-dependent effects of GH on the liver, is evaluated. Together, these studies of the cellular, molecular, and gene regulatory mechanisms that underlie sex-based differences in liver gene expression have provided novel insights into the physiological regulation of both xenobiotic and endobiotic metabolism.

Sex Differences in the Expression of Hepatic Drug Metabolizing Enzymes

Xenobiotics, which are absorbed into biological systems by passive diffusion across membranes are usually lipid soluble and not ideally suited for excretion. Indeed very lipophilic substances may remain in the mammalian body for many years. After a xenobiotic has been absorbed, it may undergo biotransformation to products which are rapidly excreted and therefore elimination of the compound from the animal is facilitated. However, biotransformation may also change the biological activity of the substance. Hence, the metabolic fate of the compound can have an important bearing on its toxic potential, the disposition of the compound in the body and the excretion of the compound. The metabolic reactions involved are usually divided into phase 1 and phase 2 reactions, the latter being conjugation reactions. The products of metabolism are usually more water soluble than the original compound. Although usually detoxifying, these reactions, especially phase 1 ones, sometimes increase toxicity.


Keywords:

biotransformation;
metabolism;
Phase 1;
Phase 2;
conjugation;
cytochrome;
hydroxylation;
oxidation;
dealkylation

Biotransformation of Xenobiotics

Nowadays, research on medicinal plants has attracted a lot of attention globally. A number of evidence has been accumulated to demonstrate promising potential of medicinal plants used in various traditional, complementary, and alternative systems. In recent years, a medicinal plant, Andrographis paniculata, and its major active phytochemicals have been extensively studied for several pharmacological activities. To understand the mechanism of action, researches have to be carried out at molecular levels. The present review aims at compiling consequential compendium of pharmacological benefits of health on this plant and its major diterpenoid constituent andrographolide that have been tested in various experimental models using modern scientific methodologies.

/pdf/pharmacological-aspects-of-andrographis-paniculata-on-health-4l183zkrcw.pdf

Pharmacological Aspects of Andrographis paniculata on Health and Its Major Diterpenoid Constituent Andrographolide

Ulcerative colitis (UC) is an idiopathic relapsing inflammatory disease. Although the etiology of UC remains unclear, it could be characterized by inflammation of the intestinal mucosa, starting from the rectum and potentially involving the entire colon. The immune response and inflammatory pathway of UC have shown that tissue damage is driven by dynamic and complexes of cells and cytokines. Various types of cells, including antigen-presenting cells (dendritic cells and macrophages), T helper cells, regulatory T cells, and natural killer T cells, play a crucial role in UC pathogenesis by regulation, suppression, and maintenance of inflammation. Moreover, cytokine networks become an important part due to their signaling function, which is indispensable for cell communication. Pro-inflammatory cytokines [tumor necrosis factor-α, interleukin (IL)-1, IL-6, IL-9, IL-13, and IL-33] play significant roles in upregulation, while anti-inflammatory cytokines (transforming growth factor-β, IL-10, and IL-37) play significant roles in downregulation of disease progression. The pathogenesis of UC consists of immuno-inflammatory pathways related to the multiple components of the intestine, including the epithelial barrier, commensal microflora, antigen recognition, dysregulation of immunological responses, leukocyte recruitment, and genetic factors. The understanding of immuno-inflammatory pathways of UC might lead to the development of a specific therapy and/or a novel treatment that could be more efficient.

Immune response and inflammatory pathway of ulcerative colitis

The steroid hormones progestagens, estrogens, androgens, and glucocorticoids as well as their precursor cholesterol are required for successful establishment and maintenance of pregnancy and proper development of the fetus The human placenta forms at the interface of maternal and fetal circulation It participates in biosynthesis and metabolism of steroids as well as their regulated exchange between maternal and fetal compartment This review outlines the mechanisms of human placental handling of steroid compounds Cholesterol is transported from mother to offspring involving lipoprotein receptors such as low-density lipoprotein receptor (LDLR) and scavenger receptor class B type I (SRB1) as well as ATP-binding cassette (ABC)-transporters, ABCA1 and ABCG1 Additionally, cholesterol is also a precursor for placental progesterone and estrogen synthesis Hormone synthesis is predominantly performed by members of the cytochrome P-450 (CYP) enzyme family including CYP11A1 or CYP19A1 and hydroxysteroid dehydrogenases (HSDs) such as 3β-HSD and 17β-HSD Placental estrogen synthesis requires delivery of sulfate-conjugated precursor molecules from fetal and maternal serum Placental uptake of these precursors is mediated by members of the solute carrier (SLC) family including sodium-dependent organic anion transporter (SOAT), organic anion transporter 4 (OAT4), and organic anion transporting polypeptide 2B1 (OATP2B1) Maternal-fetal glucocorticoid transport has to be tightly regulated in order to ensure healthy fetal growth and development For that purpose, the placenta expresses the enzymes 11β-HSD 1 and 2 as well as the transporter ABCB1 This article also summarizes the impact of diverse compounds and diseases on the expression level and activity of the involved transporters, receptors, and metabolizing enzymes and concludes that the regulatory mechanisms changing the physiological to a pathophysiological state are barely explored The structure and the cellular composition of the human placental barrier are introduced While steroid production, metabolism and transport in the placental syncytiotrophoblast have been explored for decades, few information is available for the role of placental-fetal endothelial cells in these processes With regard to placental structure and function, significant differences exist between species To further decipher physiologic pathways and their pathologic alterations in placental steroid handling, proper model systems are mandatory

/pdf/physiology-and-pathophysiology-of-steroid-biosynthesis-16qcrile2b.pdf

Physiology and Pathophysiology of Steroid Biosynthesis, Transport and Metabolism in the Human Placenta

Regulation of the expression of two female-predominant CYP3A mRNAs (CYP3A41 and CYP3A44) in mouse liver by sex and growth hormones.

The effect of abiotic and biotic elicitors (methyl jasmonate, chitosan, salicylic acid, Agrobacterium, and yeast extract) at various concentrations on total isoflavonoid accumulation was studied in the hairy root cultures of Pueraria candollei. All elicitors stimulated isoflavonoid production. Yeast extract (0.5 mg/ml) was the most efficient giving total isoflavonoids at 60 ± 1 mg/g dry wt, which was 4.5-fold higher than control hairy roots on day 3 of elicitation.

Kanokwan Jarukamjorn

Papers

Pharmacological Aspects of Andrographis paniculata on Health and Its Major Diterpenoid Constituent Andrographolide

Immune response and inflammatory pathway of ulcerative colitis

Physiology and Pathophysiology of Steroid Biosynthesis, Transport and Metabolism in the Human Placenta

Regulation of the expression of two female-predominant CYP3A mRNAs (CYP3A41 and CYP3A44) in mouse liver by sex and growth hormones.

Improved isoflavonoid production in Pueraria candollei hairy root cultures using elicitation